Obesity markedly increases the risk of developing hypertension, but the mechanisms which lead to obesity-related hypertension are poorly understood. The long-term objectives of this proposal are to evaluate the role of non-esterified fatty acids (NEFA) in the genesis of obesity-related hypertension. In particular, the relationship between splanchnic production of NEFA and blood pressure regulation will be explored. Four specific aims are proposed. The relationship between splanchnic and systemic NEFA production, sympathetic nerve activity and blood pressure in lean individuals and subjects with visceral and lower body obesity will be determined. The suppressibility of NEFA production in these individuals will also be compared to measurements of sympathetic activity. The effects of dietary induced weight reduction and pharmacologic therapy on splanchnic and systemic NEFA production, sympathetic nerve activity and blood pressure will be assessed. Ninety women will be studied. Thirty lean control subjects, thirty individuals with lower body obesity and thirty individuals with upper obesity will be studied. Body fat distribution will be characterized using DEXA and CT scanning and blood pressure will be assessed using ambulatory monitoring. Splanchnic and systemic NEFA production will be determined using infusions of 3H-palmitate following hepatic venous catheterization. Renal norepinephrine (NE) spillover will be measured and NE production will be estimated using kinetic analysis of norepinephrine (NE) spillover will be measured and NE production will be estimated using kinetic analysis of the decay of infused 3H-NE. Suppressibility of NEFA production will be determined during a hyperinsulinemic, euglycemic clamp study. Measurements of both NEFA production and NE kinetics will be repeated during the clamp study. Thirty women will undergo a sixteen week supervised weight loss program entailing weekly meetings with a dietitian and dietary supervision. Body composition, blood pressure, NEFA production and suppressibility and NE spillover and kinetics will be measured after completion of the weight loss program to determine the relationship between the hypotensive effects of weight loss and changes in NEFA metabolism. A second intervention study will be performed in third women to test the effects of pharmacologic lowering of NEFA production on blood pressure and NE kinetics. Individuals will be treated with nicotine acid and troglitazone to reduce fasting NEFA levels by 50%. Studies will be repeated at the conclusion of the pharmacologic intervention. Taken together, these studies should provide information regarding the role of splanchnic NEFA in the genesis of obesity-related hypertension.